Figure 1 Legend:
Variant protein linear diagrams: (A) Patients 1 and 2 were found to have
15-base pair in-frame deletions in exon 12 of BRAF, resulting in a
predicted deletion of five amino acids from the protein kinase domain of
the protein. This area represents the β3/αC-helix loop of the kinase
domain and is an important structural region allowing for conformational
changes between the αC-helix-in and αC-helix-out conformations. In-frame
deletions in this area have been shown by molecular modeling to shorten
the loop, locking the αC-helix in the αC-helix-in conformation which
favors BRAF protein dimerization and activation of the downstream MAPK
pathway. The most common LCH pathogenic variant, p.V600E, is shown for
reference. 11 (B) Patient 3 had a 15-base pair
in-frame deletion in exon 2 of MAP2K1, resulting in a predicted deletion
of five amino acids from the N-terminal negative regulatory domain of
the protein which presumably derepresses the kinase domain, leading to
subsequent MAPK pathway activation. 12
Conflict of interest: The authors report no conflict of
interest.
Acknowledgements: The authors thank the generosity of the
patients and their family who agreed to share their information with the
public.
Source of funding: no source of funding was available for this
report.